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"Storr, G. M"
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Experiences and challenges of people with multiple sclerosis and low attendance to clinical follow-up: a qualitative study
Background
Many people with Multiple Sclerosis (MS) in Europe face limited treatment and care access. Research on the challenges faced by people who do not access specialized MS care and treatment is limited, leaving a gap in understanding the experiences and challenges of those who do not attend specialized care. Thus, we aimed to explore the experiences of people with MS who do not attend regular clinical follow-up in specialized MS clinics in Denmark, with a special focus on self-care.
Methods
A qualitative study was conducted using individual interviews and thematic analysis, following Braun and Clarke’s approach. Data were collected in Denmark between September 2022 and February 2024 through semi-structured interviews, guided by the interview guide development principles outlined by Kvale and Brinkmann. NVivo was used to support data management and coding during the analysis.
Results
15 participants were included in the study, of whom 73% were female, 53% had relapsing-remitting MS, and 60% were not receiving any treatment. 53% were using mobility aids, most of them were married, had adult children, medium education level, and were on disability pensions. Participants were evenly distributed across regions of Denmark. The analysis identified two main themes that shed light on the experiences and challenges of people with MS who do not regularly attend clinics. Theme 1, Cognitive and Bodily Disruption, highlights how participants experience cognitive and physical fragmentation, requiring constant adjusting and negotiating self-care strategies. Theme 2, Disruptions in Care Pathways, explores how aging and fragmented healthcare gaps impact self-care management.
Conclusion
People with MS who do not attend regular specialized care face physical and cognitive challenges that impact their self-care abilities. Participants experienced disruptions in care pathways with inadequate symptom management tools, felt undervalued by the health care system, and struggled with limited recognition of symptoms and disease progression, all of which hindered their ability to manage their health and daily life effectively.
Journal Article
Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases
The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC
of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound
which displayed increased potency with an IC
of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-
]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.
Journal Article
Cannabis Use Provides Symptom Relief in Patients with Inflammatory Bowel Disease but Is Associated with Worse Disease Prognosis in Patients with Crohn's Disease
Cannabinoids are used by patients with inflammatory bowel disease (IBD) to alleviate their symptoms. Little is known on patient motivation, benefit, or risks of this practice. Our aim was to assess the extent and motives for Cannabis use in patients with IBD and the beneficial and adverse effects associated with self-administration of Cannabis.MethodsConsecutive patients with IBD (n = 313) seen in the University of Calgary from July 2008 to March 2009 completed a structured anonymous questionnaire covering motives, pattern of use, and subjective beneficial and adverse effects associated with self-administration of Cannabis. Subjects who had used Cannabis specifically for the treatment of IBD or its symptoms were compared with those who had not. Logistic regression analysis was used to identify variables predictive of poor IBD outcomes, specifically surgery or hospitalization for IBD.ResultsCannabis had been used by 17.6% of respondents specifically to relieve symptoms associated with their IBD, the majority by inhalational route (96.4%). Patients with IBD reported that Cannabis improved abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%), and diarrhea (28.6%), although side effects were frequent. The use of Cannabis for more than 6 months at any time for IBD symptoms was a strong predictor of requiring surgery in patients with Crohn's disease (odds ratio = 5.03, 95% confidence interval = 1.45–17.46) after correcting for demographic factors, tobacco smoking status, time since IBD diagnosis, and biological use. Cannabis was not a predictor for hospitalization for IBD in the previous year.ConclusionsCannabis use is common in patients with IBD and subjectively improved pain and diarrheal symptoms. However, Cannabis use was associated with higher risk of surgery in patients with Crohn's disease. Patients using Cannabis should be cautioned about potential harm, until clinical trials evaluate efficacy and safety.
Journal Article
Smoking quit success genotype score predicts quit success and distinct patterns of developmental involvement with common addictive substances
Genotype scores that predict relevant clinical outcomes may detect other disease features and help direct prevention efforts. We report data that validate a previously established v1.0 smoking cessation quit success genotype score and describe striking differences in the score in individuals who display differing developmental trajectories of use of common addictive substances. In a cessation study, v1.0 genotype scores predicted ability to quit with
P
=0.00056 and area under receiver-operating characteristic curve 0.66. About 43% vs 13% quit in the upper vs lower genotype score terciles. Latent class growth analyses of a developmentally assessed sample identified three latent classes based on substance use. Higher v1.0 scores were associated with (a) higher probabilities of participant membership in a latent class that displayed low use of common addictive substances during adolescence (
P
=0.0004) and (b) lower probabilities of membership in a class that reported escalating use (
P
=0.001). These results indicate that: (a) we have identified genetic predictors of smoking cessation success, (b) genetic influences on quit success overlap with those that influence the rate at which addictive substance use is taken up during adolescence and (c) individuals at genetic risk for both escalating use of addictive substances and poor abilities to quit may provide especially urgent focus for prevention efforts.
Journal Article
Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro
Lymphovascular invasion (LVI), encompassing blood and lymphatic vessel invasion, is an important event in tumourigenesis. Macrophages within the tumour microenvironment are linked to the presence of LVI and angiogenesis. This study investigates the role of macrophage-derived, caspase-1-dependent interleukin-1beta (IL-1β) in an in vitro model of LVI. IL-1β significantly augmented the adhesion and transmigration of breast cancer cell lines MCF7 and MDA-MB-231 across endothelial cell barriers. MDA-MB-231 and MCF7 showed a higher percentage of adhesion to lymphatic endothelial cells than blood endothelial cells following endothelial cell IL-1β stimulation (
P
< 0.001 and
P
< 0.0001, respectively). Supernatants from activated macrophages increased the adhesion of tumour cells to lymphatic and blood endothelium. Secretion of IL-1β was caspase-1 dependent, and treatment with caspase-1 inhibitor reduced IL-1β production by 73% and concomitantly reduced tumour cell adhesion to levels obtained with resting macrophages. Transmigration of MDA-MB-231 cells across blood and lymphatic endothelial monolayers was significantly increased following IL-1β stimulation. Furthermore, supernatants from activated macrophages increased transmigration of MDA-MB-231 cells across endothelial monolayers, which was abolished by caspase-1 inhibition. IL-1β stimulation of tumour cells significantly increased their migratory ability and a significant increase in migration was observed when MDA-MB-231 cells were stimulated with macrophage conditioned media (two of three donors). Results demonstrate that macrophage production of IL-1β plays an important role in the migration of breast cancer cells and their adhesion to, and transmigration across, blood and lymphatic endothelial cells. Results suggest that IL-1β may play a role in the adhesion to lymphatic endothelial cells in particular.
Journal Article
Thioredoxin System Protein Expression in Carcinomas of the Pancreas, Distal Bile Duct, and Ampulla in the United Kingdom
Background: Poor survival outcomes in periampullary cancer highlight the need for improvement in biomarkers and the development of novel therapies. Redox proteins, including the thioredoxin system, play vital roles in cellular antioxidant systems. Methods: In this retrospective study, thioredoxin (Trx), thioredoxin-interacting protein (TxNIP), and thioredoxin reductase (TrxR) protein expression was assessed in 85 patients with pancreatic ductal adenocarcinoma (PDAC) and 145 patients with distal bile duct or ampullary carcinoma using conventional immunohistochemistry. Results: In patients with PDAC, high cytoplasmic TrxR expression was significantly associated with lymph node metastasis (p = 0.033). High cytoplasmic and nuclear Trx expression was significantly associated with better overall survival (p = 0.018 and p = 0.006, respectively), and nuclear Trx expression remained significant in multivariate Cox regression analysis (p < 0.0001). In distal bile duct and ampullary carcinomas, high nuclear TrxR expression was associated with vascular (p = 0.001) and perineural (p = 0.021) invasion, and low cytoplasmic TxNIP expression was associated with perineural invasion (p = 0.025). High cytoplasmic TxNIP expression was significantly associated with better overall survival (p = 0.0002), which remained significant in multivariate Cox regression analysis (p = 0.013). Conclusions: These findings demonstrate the prognostic importance of Trx system protein expression in periampullary cancers.
Journal Article
Calpain system protein expression in carcinomas of the pancreas, bile duct and ampulla
Background
Pancreatic cancer, including cancer of the ampulla of Vater and bile duct, is very aggressive and has a poor five year survival rate; improved methods of patient stratification are required.
Methods
We assessed the expression of calpain-1, calpain-2 and calpastatin in two patient cohorts using immunohistochemistry on tissue microarrays. The first cohort was composed of 68 pancreatic adenocarcinomas and the second cohort was composed of 120 cancers of the bile duct and ampulla.
Results
In bile duct and ampullary carcinomas an association was observed between cytoplasmic calpastatin expression and patient age (
P
= 0.036), and between nuclear calpastatin expression and increased tumour stage (
P
= 0.026) and the presence of vascular invasion (
P
= 0.043). In pancreatic cancer, high calpain-2 expression was significantly associated with improved overall survival (
P
= 0.036), which remained significant in multivariate Cox-regression analysis (hazard ratio = 0.342; 95% confidence interva l = 0.157-0.741;
P
= 0.007). In cancers of the bile duct and ampulla, low cytoplasmic expression of calpastatin was significantly associated with poor overall survival (
P
= 0.012), which remained significant in multivariate Cox-regression analysis (hazard ratio = 0.595; 95% confidence interval = 0.365-0.968;
P
= 0.037).
Conclusion
The results suggest that calpain-2 and calpastatin expression is important in pancreatic cancers, influencing disease progression. The findings of this study warrant a larger follow-up study.
Journal Article